To elucidate the molecular mechanisms of biological fusion we have studied the lipid-involving fusion intermediates. Membrane fusion mediated by viral envelope glycoproteins (either baculovirus gp64 or influenza hemagglutinin, HA), includes a low pH triggering event, apparently independent of membrane lipid composition. We have identified a specific stage of fusion which is subsequent to the low pH-induced changes in HA and gp64 conformation, but precedes hemifusion and fusion pore formation. This stage, actual membrane merger, does not require low pH but is still protein-dependent and may be inhibited by trypsin and N-ethylmaleimide (gp64-mediated fusion) and by proteinase K (hemagglutinin-mediated fusion). Membrane merger can be reversibly modulated by changes in membrane lipid composition in a specific correlation with the effective molecular shape of the lipids. Cone-shaped lipids (e.g., oleic acid, OA) promoted, and inverted cone-shaped lipids (e.g., lysophosphatidylcholine, LPC) inhibited fusion, if added to the contacting monolayers of the fusing membranes. These effects are additive, since the exogenous lipids cancel each other if added simultaneously. Addition of LPC caused an increase in the number of fusion proteins that must undergo a low pH conformational change in order to drive fusion in the presence of lysolipids. In contrast, OA decreased the number of the activated fusion proteins required. Our data indicate that the different membrane fusion systems including fusion of purely lipid bilayers, involve a consecutive formation of transient and local highly bent intermediates, stalks and pores. Energy of these intermediates and, consequently, the rate and extent of fusion depend on the propensity of the corresponding monolayers of membranes to bend in the required directions.